JPH0348166B2 - - Google Patents
Info
- Publication number
- JPH0348166B2 JPH0348166B2 JP61025268A JP2526886A JPH0348166B2 JP H0348166 B2 JPH0348166 B2 JP H0348166B2 JP 61025268 A JP61025268 A JP 61025268A JP 2526886 A JP2526886 A JP 2526886A JP H0348166 B2 JPH0348166 B2 JP H0348166B2
- Authority
- JP
- Japan
- Prior art keywords
- skin
- producing
- medical
- medical agent
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9728—Fungi, e.g. yeasts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Dermatology (AREA)
- Botany (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cosmetics (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
- Compounds Of Unknown Constitution (AREA)
Description
本発明は、新規な微生物トリコスポロン
(Trichosporon)カシワヤマ株(微工研菌寄第
4821号:以下カシワヤマ株と略稱する)の培養液
を常法に従つて濾過除菌して得られた無菌上澄
液、または該上澄液をさらに常法によつて濃縮し
た濃縮液若しくはその乾燥物からなる、皮膚用医
療剤に関する。
ちなみに本発明に於て使用する「皮膚用医療
剤」という用語は、それが呈する作用・効果の観
点から、広く所謂「化粧品」と呼ばれているもの
を包含する。すなわち、培養後の処理により得ら
れた液状物または固状物を有効成分とし、これを
担体例えば皮膚用のクリームまたは軟膏基材等に
含有せしめたものは皮膚用の医療剤として有用な
るのみならず、化粧品としても有用なものであ
る。
本発明で使用する新規な微生物トリコスポロン
カシワヤマ株は酵母にすると考えられる。しか
し、菌の同定にあたり、たとえば次のような文
献、
(1) ア ニユー キー ツウ ザ イースト
(1974)
(A new key to THE YEASTS)
(2) ア ガイド ツウ アイデンテイスアイング
アンド クラスフアイング イースト
(1979)
(A guide to identifying and
classifyjng yeasts)
によるときは不完全菌に分類される場合もあり、
ゲオトリカム(Geotricum)属又はエンドミコプ
シス(Endomycopsis)属に属する菌として同定
されることもあり得る。
本発明で使用する新規な微生物は、添付の写真
図に示す通り、ジユズ状に連なる分節胞子と偽菌
糸と有する点で特異的なものである。
該微生物の発酵生産物をさらに詳しくは培養液
の上澄液などは、皮膚に対し顕著な医療効果を奏
する。なお、前記医療効果を呈する有効物質の本
体は、未だ完全に解明されていない。前記の如く
本発明の微生物培養液の無菌上澄液、その濃縮又
は乾燥物は、その単独使用又はそれらと適宜な担
体とを用い皮膚に適用した場合、下記のような有
用性(医療的効果)を呈する:
(1) 発酵液は弱酸性(PH4.5〜5.5)を呈するが皮
膚に対し無害であり、特に皮膚脂肪膜の細菌制
御作用をはじめとする皮膚の保護作用を有す
る。
(2) 角層細胞からの過度な角片の剥離を防ぎ、同
時に角層の水分を保持する。その結果健全な皮
膚自体の持つ特性(「うるおい」「弾力性」)を
維持することができる。
(3) 表皮細胞の脂質代謝をコントロールすること
により、適正な角質生成及び円滑な表皮細胞の
増殖と分化とを促す。
(4) 特に脂性皮膚に対しては過度な皮脂分泌を抑
え、脂肪膜の厚化を防ぎ、従つつて毛嚢から皮
膚表面への皮脂の拡散を促進するので坐瘡をは
じめとする多脂肪性皮膚症に対して予防的効果
を有する。
(5) 網状層の膠原線維を強化し又は膨化させ、そ
の上層の水分を保持するため、皮膚の正常な硬
度及び弾力性を促す。
(6) 血液循環を改善する。すなわち、皮膚の新陳
代謝を促進し、同時に皮膚老廃物の静脈への運
搬、排泄を活発にする。それに伴い、メラニン
色素の体外排出も促進する。
(7) 光線下の酸化にもとづく皮膚疾患に対し、脂
肪膜抗酸化剤的作用を有し、シミ等のように異
常沈着しているメラニン色素の褐色を促す。特
に赤外線照射、ビタミンE内服等と併用すると
相乗的に働き、接触皮膚炎、シミ、その他日光
過敏症による色素異常に対し、単なる予防に
とゞまらず治療的効果を有する。
本発明で使用するトリコスポロン カシワヤマ
株は、従来民間療法で用いられているある種の健
康飲料を分離源として得られた新規な菌株であ
る。この飲料は、一地方において50有余年にわた
つて伝承されてきた乳酸菌飲料の一種であり、乳
酸菌及び数種の酵母よりなる混合系の発酵生産物
である。この飲料については、また皮膚塗付時に
効果があるという知見が一部あつた。そこで皮膚
に対する有効性の実証という観点から、この混合
系発酵生産物を構成する個々の菌群の特性を鋭意
研究した結果、カシワヤマ株の産するある種の未
知成分が、特に皮膚に対して有効な作用を示すこ
とを併せ見出した。
本発明のカシワヤマ株は、高濃度乳酸酸性で長
期保存し、耐酸性及び乳酸の強い酸化的分解能を
獲得したときにのみ、ある種の有効成分を産出す
る。即ち、本発明のカシワヤマ株は、前述の乳酸
菌飲料から該株の純粋化を、3回(又はそれ以
上)繰返すことによりスクリーニングを行つた
後、更に高濃度乳酸含有ホエー培地(乳酸2.5〜
3.0w/v%、PH3.0〜3.3)にて25℃で48時間振と
う培養を行ない、乳酸脱水素酵素活性又は乳酸の
酸化的分解能を指標として、再度、菌株の選択を
行つた結果創製されたものである。
このようにして得られたカシワヤマ株は、同属
又は類似の標準菌に比較して、その皮膚有効性に
おいて著しい臨床的な差異を有するものである。
本発明で使用するカシワヤマ株の菌学的性質は
次の通りである:
(A) 形態学的諸特性
(1) 形態及び大きさ(麦芽汁、MY液体培地)
25℃、3日後に(3−4μ)×(3−20μ)の
矩形(rectangular)乃至は卵形(oval)の
細胞であり、5日以降においては不規則な形
状を呈し、やがて菌糸状となる。
(2) 偽菌糸形成(バレイシヨ抽出液寒天培地に
おけるスライド培養)
偽菌糸状(pseudohyphal or
pseudomycelial)を呈する。ジグザグ状の
特徴的な分節胞子(arthrospore)を有する
が、分生子柄は持たない。
(3) 子のう胞子 有せず
(4) 射出胞子 有せず
(B) 培養学的諸特性
(1) 寒天斜面培地上のコロニー(麦芽汁及び
MY寒天培地)
無光沢(dull)、白色(white)、羽状
(hairy)、粗造(rough)表面で、極めてな
めめらか(soft)である。隆起せず平坦で周
辺は毛様状(ciliate)を呈する。
(2) 液体培地における皮膜(麦芽汁及びMY液
体培地)
白色(white)、羽状(hairy)、しわ状で
かたい皮膜を形成する。
(3) 培地中の栄養源から芳香を形成する。
(4) 生育好適PH4.0〜6.0、生育好適温度20〜30
℃
(C) 生理学的諸特性
(1) 糖類発酵性
グルコース、ガラクトース、シユクロー
ス、ラクトース、トレハロース、ラフイノー
ス、イヌリンのすべてに対し非発酵性。
(2) 糖類資化性(同化性)
D−グルコース(D−Glucose) +
D−ガラクトース(D−Galactose) +
麦芽糖(Maltose) −
ラフイノース(Raffinose) −
シヨ糖(Sucrose) −
乳糖(Lactose) −
乳酸ナトリウム(Na Lactate) +
D−キシロース(D−Xylose) +
エリトリツト(Erythritol) −
D−マンニツト(D−Mannitol) +
L−ソルボース(L−Sorbose) +
イノシツト(Inositol) −
トレハロース(Treharose) −
D−アラビノース(D−Arabinose) −
L−アラビノース(L−Arabinose) −
コハク酸ナトリウム(Na Succinate) +
クエン酸ナトリウム(Na Citrate) +
酢酸ナトリウム(Na Acetate) +
イヌリン(Inulin) −
可溶性デンプン(Soluble Starch) −
エタノール(Ethanol) +
グリセリン(Glycerol) +
セロビオース(Cellobiose) −
(注)+ 資化性を有する
− 資化性を有しない
(3) 硝酸塩の資化性 資化せず
(4) 亜硝酸塩の資化性 資化せず
(5) エチルアミンハイドロクロライドの資化性
資化せず
(6) グルコシド(アルブチン)の分解 資化する
(7) デンプン様類似物質の生成 生成せず
(8) 色素 生成せず
(9) エステル生成 生成する
(10) リトマスミルク反応 非凝固
(11) ビタミン要求性 要求せず
(12) 食塩耐性 限界濃度 6〜8
(W/V)%
(13) 最適温度 25℃
(14) 最適PH 5.0
(15) 尿素分解性 分解せず
(16) 50%、60%(w/w)グルコース−イー
ストエキス寒天での生育 生育せず
(17) 37℃での生育 生育せず
(18) シクロヘキシミド耐性 耐性あり
(19) 油脂分解性 分解する
(D) その他の菌学的特性
(1) 芳香生産性
カシワヤマ株は、中性香気成分の産生にお
いて著しい特性を持つている。その中性香気
成分のガスクロマトグラフ分析によれば、エ
タノール、酢酸エチル、イソプロピルアルコ
ール、イソ酢酸プロピル、イソブチルアルコ
ール、イソ酢酸ブチル、イソアミルアルコー
ル、イソ酢酸アミルを主成分とする、いわゆ
るリンゴ香である。
又、カシワヤマ株は従来芳香生産性が認め
られている酵母に比較して、高級アルコール
の生産のみならず、そのエステル化率の高い
ことが特徴である。
これら中性香気成分の生産における最適条件
は、下記の通りである:
(a) 初発PH4.0〜5.0及び発酵中の低PHの維持
(b) 培地中の総窒素量;400〜500mg/;
無機窒素源としては、硫酸アンモニウ
ム、硝酸アンモニウム、塩化アンモニウ
ム;有機窒素源としては酵母エキス、カザ
ミノ酸、ペプトンが適している。更に、ロ
イシン、イソロイシン、バリン、フエニル
アラニン等のアミノ酸添加効果が顕著であ
る。
(c) 炭素源の選択:グリコース、ガラクトー
ス、エタノール、グリセロース等が適して
いる。糖濃度は5%、
(d) 菌接種率 1〜2%
(e) 培養は25〜30℃、静置培養
(2) 有機酸生成
グルコースよりギ酸、プロピオン酸、n−
酢酸、コハク酸及びクエン酸を生成する。
次に本発明のトリコスポロン カシワヤマ株
と、公知種との相違点を列挙すれば、以下の通り
である。
(A) 形態学的にはコロニーの性状、菌糸や、分節
胞子の形態などから、トリコスポロン ペニシ
レイタム(現在、ゲオトリカム ペニシレイタ
ム)に酷似しているが、
分生子柄が不明瞭である、
グルコース、ガラクトースの発酵性を全く
有しない、
D−マンニトール、クエン酸を資化する、
エチル、イソプロピルアルコール、イソ酢
酸プロピル、イソブチルアルコール、イソ酢
酸ブチル、イソアミルアルコール、イソ酢酸
アミルなどの高級アルコール及びそのエステ
ルを主成分とする、中性香気成分を生成す
る、
という点において相違する。
(B) 同様に、ゲオトリカム、キヤンデイダムとも
形態学的によく類似しているが、
グルコースの発酵性を全く有しない、
アルブチン(Arbutin、Hydroquinone−
β−D−Glucopyranoside)の分解能を有す
る、
DL−乳酸、コハク酸の資化性が強い、
などの点で公知種と異なる。
(C) さらにエンドミコプシス オベテンシス(現
在、ツエンデラ オベテンシス)とは、
アルブチン分解能を有する、
ビタミン要求性を有しない、
D−キシロース、D−マンニトール、クエ
ン酸を資化する、
出芽形態が異なり、子のう胞子を形成しな
い、その他形態学的に異なる、
などの点で、相違する。
カシワヤマ株を使用して新規な皮膚用医療剤を
製造するには、慣用の酵母培養培地を用い得る。
好適な一例として次の組成の培地、即ちグルコ
ース0.3%(w/v)、スキムミルク0.5%(w/
v)、イーストエキス0.05%(w/v)を含有す
るPH4.0〜6.0の固形または液体培地を用い、それ
を、20〜30℃で約24時間振盪又は静置培養したも
のを種菌とし、同培地で20〜30℃で3〜7日間静
置又は振盪培養する。
同培養液は、ついで常法により例えばメンブラ
ンフイルターにて濾過除菌し、無菌上澄液を濃縮
し(例えば減圧濃縮し)、好適には2〜25倍濃縮
液とする。
当該濃縮液は、さらに常法により殺菌工程を経
たのち常温又は冷蔵保存する。
本発明で製造される無菌上澄液の一例は、第1
表に示される通りの諸性質を有していた。
第1表
カシワヤマ株による培養上澄液の無菌ろ過精製
物は、少量のアミノ酸、糖質、脂質を含む。さら
に総窒素として0.005〜0.015%、総リンとして
0.004〜0.014%を含む。
1 性 状 無色〜微黄色の透明な液で、わずか
に特異な芳香を有する。
2 確認試験 本品20mlを水浴上で約5mlに
なるまで蒸発させ、この液にニンヒドリン試
液1mlを加えて30分間加熱するとき、液は紫
色を呈する。
と同様に蒸発させた液に硝酸5mlを加
え、20分間煮沸する。冷後10%水酸化ナトリ
ウム溶液で中和したのち、モリブデン酸アン
モニウム試液2mlを加え、加熱するとき、液
は黄色を呈する。冷後、この液に10%水酸化
ナトリウム溶液を追加するとき、液は無色に
なる。
5mlをとり、インドール10mgおよび塩酸2
mlを加え、よく振り混ぜたのち、10分間加熱
すると、液は赤色を呈する。
3 物性値 比 重(d25D):1.000〜1.015
屈折率(d25 25):1.330〜1.340
PH (25°):4.5〜5.5
4 蒸発残留物 0.5〜2.0%
本発明で製造される無菌上澄液の濃縮物(2倍
濃縮物)の一例は、第2表に示される通りの分析
値を有していた。
The present invention is directed to a novel microorganism, Trichosporon, strain Kashiwayama.
No. 4821: A sterile supernatant obtained by filtering and sterilizing the culture solution of Kashiwayama strain (hereinafter referred to as Kashiwayama strain), or a concentrated liquid obtained by further concentrating the supernatant by a conventional method. This invention relates to a medical drug for the skin consisting of a dried product thereof. Incidentally, the term "dermatological medical agents" used in the present invention includes what is broadly called "cosmetics" from the viewpoint of the actions and effects they exhibit. In other words, if the active ingredient is a liquid or solid substance obtained by treatment after culturing and is contained in a carrier such as a cream or ointment base material for the skin, it is useful as a medical agent for the skin. It is also useful as a cosmetic product. The novel microorganism Trichosporon kashiwayama strain used in the present invention is considered to be yeast. However, when identifying bacteria, for example, the following documents are available: (1) A new key to THE YEASTS (1974) (2) A guide to identifying and classifying yeast (1979) ) (A guide to identifying and
classificationjng yeasts), it may be classified as Deuteromyces,
It may also be identified as a fungus belonging to the genus Geotricum or Endomycopsis. As shown in the attached photograph, the novel microorganism used in the present invention is unique in that it has segmented spores and pseudohyphae that are arranged in a cascade shape. The fermentation product of the microorganism, more specifically the supernatant of the culture fluid, has a remarkable medical effect on the skin. Incidentally, the substance of the effective substance that exhibits the above-mentioned medical effects has not yet been completely elucidated. As mentioned above, the sterile supernatant of the microbial culture of the present invention, its concentrated or dried product, when used alone or when applied to the skin with an appropriate carrier, has the following usefulness (medical effects). ): (1) Although the fermented liquid exhibits weak acidity (PH4.5 to 5.5), it is harmless to the skin, and has skin protective effects, including the ability to control bacteria in the skin fat film. (2) Prevents excessive exfoliation of horny pieces from stratum corneum cells and at the same time retains moisture in the stratum corneum. As a result, the properties of healthy skin itself ("moisture" and "elasticity") can be maintained. (3) By controlling the lipid metabolism of epidermal cells, it promotes proper keratin production and smooth proliferation and differentiation of epidermal cells. (4) Especially for oily skin, it suppresses excessive sebum secretion, prevents the thickening of fatty membranes, and promotes the diffusion of sebum from hair follicles to the skin surface, so it can prevent acne and other fatty skin. It has a preventive effect against sexual dermatoses. (5) It strengthens or swells collagen fibers in the reticular layer and retains moisture in the upper layer, thereby promoting normal hardness and elasticity of the skin. (6) Improve blood circulation. In other words, it promotes skin metabolism and at the same time activates the transportation and excretion of skin wastes into the veins. Along with this, it also promotes the excretion of melanin pigment from the body. (7) It acts as a fatty membrane antioxidant against skin diseases caused by oxidation under sunlight, and promotes the browning of melanin pigments that are abnormally deposited in spots, etc. In particular, when used in combination with infrared irradiation, vitamin E, etc., it works synergistically, and has not only a mere preventive effect but also a therapeutic effect on contact dermatitis, age spots, and other pigment abnormalities caused by hypersensitivity to sunlight. The Trichosporon Kashiwayama strain used in the present invention is a novel strain obtained from a certain type of health drink conventionally used in folk medicine. This drink is a type of lactic acid bacteria drink that has been passed down in one region for over 50 years, and is a fermented product of a mixed system consisting of lactic acid bacteria and several types of yeast. There was also some knowledge that this drink was effective when applied to the skin. Therefore, from the perspective of demonstrating its effectiveness on the skin, we conducted extensive research into the characteristics of the individual bacterial groups that make up this mixed fermentation product, and found that certain unknown ingredients produced by the Kashiwayama strain were particularly effective on the skin. We have also discovered that this effect shows a significant effect. The Kashiwayama strain of the present invention produces certain active ingredients only when it is stored for a long time in acidic conditions with high concentration of lactic acid and acquires acid resistance and strong oxidative decomposition ability of lactic acid. That is, the Kashiwayama strain of the present invention was screened by repeating the purification of the strain from the lactic acid bacteria drink three times (or more), and then purified with a whey medium containing a higher concentration of lactic acid (lactic acid 2.5~
3.0w/v%, PH3.0-3.3) at 25℃ for 48 hours with shaking culture, and strains were selected again using lactate dehydrogenase activity or lactic acid oxidative decomposition ability as indicators. It is what was done. The Kashiwayama strain thus obtained has a significant clinical difference in its skin efficacy compared to standard strains of the same genus or similar. The mycological properties of the Kashiwayama strain used in the present invention are as follows: (A) Morphological characteristics (1) Morphology and size (wort, MY liquid medium) After 3 days at 25°C (3 -4μ) x (3-20μ) rectangular or oval cells, which take on an irregular shape after 5 days and eventually become hyphal-like. (2) Pseudohyphal formation (slide culture on potato extract agar medium)
pseudomycelial). It has characteristic zigzag-shaped arthrospores, but no conidiophores. (3) Ascospores not present (4) Exjected spores not present (B) Cultural properties (1) Colonies on agar slant medium (wort and
MY Agar Medium) Dull, white, hairy, rough surface and extremely soft. It is flat without any protuberances, and the periphery is ciliate. (2) Film in liquid medium (wort and MY liquid medium) Forms a white, hairy, wrinkled, hard film. (3) Formation of aroma from nutrient sources in the medium. (4) Suitable growth pH 4.0-6.0, suitable growth temperature 20-30
°C (C) Physiological properties (1) Sugar fermentability Non-fermentable for glucose, galactose, sucrose, lactose, trehalose, raffinose, and inulin. (2) Saccharide assimilation (anabolism) D-Glucose + D-Galactose + Maltose - Raffinose - Sucrose - Lactose - Sodium Lactate + D-Xylose + Erythritol - D-Mannitol + L-Sorbose + Inositol - Treharose - D - Arabinose (D-Arabinose) - L-Arabinose (L-Arabinose) - Sodium Succinate + Sodium Citrate + Sodium Acetate + Inulin - Soluble Starch ) - Ethanol + Glycerol + Cellobiose - (Note) + Assimilated - Not assimilated (3) Nitrate assimilation Not assimilated (4) Nitrite Assimilation ability Not assimilated (5) Assimilation ability of ethylamine hydrochloride
Not assimilated (6) Degradation of glucoside (arbutin) Assimilated (7) Production of starch-like substances Not produced (8) Pigment Not produced (9) Ester production Produced (10) Litmus milk reaction Non-coagulation (11) Vitamin requirement Not required (12) Salt tolerance Limit concentration 6-8
(W/V)% (13) Optimum temperature 25℃ (14) Optimum PH 5.0 (15) Urea decomposition No decomposition (16) Growth on 50%, 60% (w/w) glucose-yeast extract agar Growth No (17) Growth at 37℃ No growth (18) Resistance to cycloheximide Tolerant (19) Degradability of fats and oils Decomposes (D) Other mycological characteristics (1) Aromatic productivity Kashiwayama strain has a neutral aroma It has remarkable properties in the production of ingredients. According to gas chromatographic analysis of its neutral aroma components, it is a so-called apple aroma whose main components are ethanol, ethyl acetate, isopropyl alcohol, propyl isoacetate, isobutyl alcohol, butyl isoacetate, isoamyl alcohol, and amyl isoacetate. In addition, the Kashiwayama strain is characterized not only in the production of higher alcohols but also in its high esterification rate, compared to yeasts that have conventionally been recognized to have aroma productivity. The optimal conditions for the production of these neutral aroma components are as follows: (a) Initial pH of 4.0 to 5.0 and maintenance of low pH during fermentation (b) Total amount of nitrogen in the medium; 400 to 500 mg/; Suitable inorganic nitrogen sources include ammonium sulfate, ammonium nitrate, and ammonium chloride; yeast extract, casamino acids, and peptone are suitable as organic nitrogen sources. Furthermore, the effect of adding amino acids such as leucine, isoleucine, valine, and phenylalanine is remarkable. (c) Selection of carbon source: Glyose, galactose, ethanol, glycerose, etc. are suitable. Sugar concentration is 5%, (d) Bacterial inoculation rate is 1-2% (e) Culture is static culture at 25-30℃ (2) Organic acid production Formic acid, propionic acid, n- from glucose
Produces acetic acid, succinic acid and citric acid. Next, the differences between the Trichosporon Kashiwayama strain of the present invention and known species are listed below. (A) Morphologically, it closely resembles Trichosporon penicillatum (currently Geotrichum penicillatum) in terms of colony characteristics, hyphae, and segmental spore morphology, but the conidiophores are unclear, and it contains glucose and galactose. The main ingredients are D-mannitol, which has no fermentability, and higher alcohols such as ethyl, isopropyl alcohol, propyl isoacetate, isobutyl alcohol, butyl isoacetate, isoamyl alcohol, and amyl isoacetate, which utilize citric acid, and their esters. They differ in that they produce neutral aroma components. (B) Similarly, Arbutin (Hydroquinone) is morphologically similar to Geotrichum and Candidum, but has no glucose fermentability.
It differs from known species in that it has the ability to decompose DL-lactic acid and succinic acid (β-D-Glucopyranoside), and has a strong ability to assimilate DL-lactic acid and succinic acid. (C) Furthermore, Endomycopsis obetensis (currently Tsendera obetensis) has the ability to decompose arbutin, does not require vitamins, assimilates D-xylose, D-mannitol, and citric acid, and has a different budding form. They differ in that they do not form cysts and are morphologically different. Conventional yeast culture media can be used to produce novel dermatological medicinal agents using the Kashiwayama strain. A suitable example is a medium with the following composition: glucose 0.3% (w/v), skim milk 0.5% (w/v).
v) Using a solid or liquid medium of pH 4.0 to 6.0 containing 0.05% (w/v) of yeast extract, it is shaken or statically cultured at 20 to 30°C for about 24 hours and used as an inoculum; Culture in the same medium at 20-30°C for 3-7 days with standing or shaking. The culture fluid is then sterilized by filtration using a membrane filter in a conventional manner, and the sterile supernatant is concentrated (for example, concentrated under reduced pressure) to preferably form a 2- to 25-fold concentrated solution. The concentrate is further sterilized by a conventional method and then stored at room temperature or refrigerated. An example of the sterile supernatant produced by the present invention is the first
It had the properties shown in the table. Table 1 The sterile filtration purified product of the culture supernatant obtained by the Kashiwayama strain contains small amounts of amino acids, carbohydrates, and lipids. Additionally 0.005-0.015% as total nitrogen and as total phosphorus
Contains 0.004-0.014%. 1. Properties: Colorless to slightly yellow, transparent liquid with a slightly unique aroma. 2 Confirmation test Evaporate 20 ml of this product on a water bath until it reaches approximately 5 ml. Add 1 ml of ninhydrin test solution to this solution and heat for 30 minutes. The liquid will turn purple. Add 5 ml of nitric acid to the evaporated liquid in the same manner as above and boil it for 20 minutes. After cooling, neutralize with 10% sodium hydroxide solution, add 2 ml of ammonium molybdate test solution, and when heated, the liquid turns yellow. After cooling, when adding 10% sodium hydroxide solution to this solution, the solution becomes colorless. Take 5ml, add 10mg of indole and 2ml of hydrochloric acid.
ml, shake well and heat for 10 minutes, the liquid will turn red. 3 Physical property values Specific gravity ( d25D ): 1.000 to 1.015 Refractive index ( d2525 ): 1.330 to 1.340 PH ( 25 °): 4.5 to 5.5 4 Evaporation residue 0.5 to 2.0% Sterile supernatant produced by the present invention An example of a liquid concentrate (2x concentrate) had analytical values as shown in Table 2.
【表】【table】
【表】【table】
【表】【table】
【表】
得られる無菌上澄液は、濃縮せずにそのまま皮
膚用医療剤に供し得る。しかしながら前記のよう
に濃縮することが保存及びその他の点で有利であ
る。また濃縮度25倍以上の濃厚物、あるいは乾燥
物も使用可能である。さらにこれをクリーム、軟
膏基材及びその他の担体と混合して用いることも
できる。
前記の無菌4倍濃縮物について分析を行つた結
果の一例では、各種アミノ酸及びビタミン類の含
有されていることが判明した。しかしながら、こ
れらの分析は、一般的項目を対象としているだけ
であるから、分析値の通りに各種成分を配合して
も、本発明の皮膚用医療剤を製造し得ない。即ち
皮膚用医療剤の有効物は、分析項目外の未知成分
によるものと推測される。
前記の無菌濃縮物(4倍濃縮)は、鶏胚テスト
による毒性試験の結果、無害であることが証明さ
れ、又2倍濃縮物での人体パツチテスト及び人体
連続皮膚刺激試験によつて皮膚に対し無害である
こと、及び家兎の眼刺激試験により無刺激性であ
ることが証明された。更に抗菌テストにより抗生
物質を含有していないことも判明した。
更に皮膚医療効果として、シミ、肌荒れ、小ジ
ワ、接触性皮膚炎、ヤケド(熱傷)に対する治療
効果のあることが判明した。
以下実施例により本発明の皮膚用医療剤及び化
粧料についてさらに具体的に説明する。
参考例 1
純水800中に、
グルコース 2.4Kg
スキムミルク 4.0Kg
イースト・エキス 0.4Kg
を含む培地(PH5.0)を、1Kl容通気撹拌発酵タ
ンク中で、常法により減菌後、これに同組成培地
10で約30時間28℃小型通気撹拌発酵タンクにて
前培養したものを種培養液として接種し、約70時
間28℃にて通気撹拌培養をおこなつた。発酵終了
後、培養液を内外食品工機株式会社製、MP293
−16型濾過機(フイルター:東洋濾紙GL−90、
0.5μ)及び、同社製のMP293−4型濾過機(メン
ブランフイルター:東洋濾紙TM−2、0.45μ)
にて、固型粒子、更には、菌体を除去した。得ら
れた濾過液を、逆浸透膜法(バイオエンジニアリ
ング社製、RO−T10型逆浸透膜装置)にて、400
に濃縮し2倍濃縮物を得た。
前述の方法を繰返し、たゞし200に濃縮し4
倍濃縮物を得た。
得られたこれらの濃縮液は、プレート式熱交換
機(岩井機械工業株式会社製あにて殺菌後、ガラ
ス容器に無菌充填し、冷蔵(5℃)して保存し
た。
得られたこれらの濃縮液の殺菌処理物から凍結
乾燥によつて得られた粉末製品を、無菌軟膏基材
と混合して皮膚用医療材を製造した。
また前記濃縮液からクリーム状の化粧料を製造
した。
これらは皮膚用医療剤ならびに化粧料として、
夫々優れた効果を示した。この点につき、以下さ
らに実施例により詳細に説明する。
実施例 1
人体パツチテスト
2倍濃縮物の約0.2gを、4cm平方のパツチ絆
に塗布し、これを年令23〜44才の50名の婦人(何
等かの皮膚症状をもち皮膚科専門病院に通院中の
患者)の左上腕内側及び背部傍脊椎部に貼付し
た。48時間後に貼付絆を除去した。除去後30分に
おいて判定した結果、左上腕内側及び背部傍脊椎
部の各部において、陽性を示した例は全くなかつ
た。
人体連続皮膚刺激試験
2倍濃縮物の約5mlを10cm2の滅菌ガーゼに含ま
せ年令23〜45才の45名の婦人(このうち35名は何
らかの皮膚症状をもつ皮膚科専門病院の外来患
者、10名は該病院の女子従業員)の右顔面頬部に
15分間塗布した。この塗布処理を40日間連続して
行つた。その結果、被験者全員については無反応
であり、紅斑等の異状を呈した例は皆無であつ
た。
兎眼刺激試験
あらかじめ眼に異常がないことの確認された白
色種家兎3頭の右眼について2倍濃縮液を、左眼
について空試験液をそれぞれ0.1mlずつ点眼し、
点眼直後、3、6、24、48及び72時間後に両眼を
スリツトランプ使用下で検査した。その結果、い
ずれの観察時においても両眼の角膜、紅彩及び結
膜に充血及びその他の異常が認められなかつた。
シミの治療試験
肝疾患の患者、婦人科系の患者、妊娠者を除外
し、顔面皮膚にシミを有し、皮膚科専門病院に通
院中の婦人621名に対し、顔面洗浄後オゾンと蒸
気による毛孔の開口を行い、本発明品(無菌上澄
液の2倍濃縮液)を、ガーゼにしませたものを、
シミ生成部位に密着させ、その上からサランラツ
プをかぶせた。ついで赤外線照射を15〜20分間行
い該品の皮膚への浸透を行つた。この処理を1週
1回、3カ月にわたつて継続した。
その結果、症状の非常に改善されたもの363名
(58.4%)、少しく改善されたもの122名(19.8
%)、改善の認められないもの133名(21.4%)、
悪化したもの1名(0.01%)、その他(別の原因
による接触性皮膚炎と認められる)2名(0.03
%)であつた。このように非常に改善されたもの
と、少しく改善されたものの合計は、約80%に達
し、非常に改善されたもの363名のうち約60%に
ついてはシミが全く消失していた。
肌荒れ、小ジワの治療試験
本発明品(2倍濃縮物)を、皮膚科専門病院に
通院中の25才以上の婦人患者の肌荒れ、小ジワの
治療に試用した。
通常、婦人は30才以上になると肌荒れ、小ジワ
を気にする。特に35〜40才において最も肌荒れ、
小ジワを気にし、30〜35才がそれに続き、40才以
上については大差がないので気にしなくなる傾向
がある。
そこで被検婦人25〜30才150名、30〜35才218
名、35〜40才248名、40〜45才172名、45才以上
174名、合計962名に対し顔面皮膚の洗浄の後に、
オゾンと蒸気により毛孔の開口を行い、ついで本
発明品(無菌上澄液の2倍濃縮)をガーゼに含ま
せたものを、顔面に密着させてかぶせ、その上を
サランラツプで蔽い、赤外線を15〜20分間照射し
該品を皮膚へ滲透させるという方法を試みた。
一回の治療処理で肌荒れが非常に改善されたも
の698名(73%)、同じく一回の治療処理で少しく
改善されたもの156名(16%)、変化のなかつたも
の72名(7%)、悪化したもの無し、その他36名
(4%)という結果を得られた。肌荒れが進むと
小ジワになり易いものであることから、肌荒れ治
療に有効である本発明品は小ジワの予防を達成す
る化粧品として有用なものであることが判明し
た。
接触性皮膚炎の治療試験
A社のアイシヤドウからB社のアイシヤドウに
使用を変更した次の日から、顔面両側の眼瞼部に
発赤と掻痒とを起し接触性皮膚炎と診断された21
才の女子に対し、皮膚科専門医により、本発明品
(2倍濃縮物)をガーゼに含ませたものを患部に
貼付した。
その際、ステロイド製剤及び消炎剤又は抗ヒス
タミン剤等を使用せず、本発明品のみを使用し
た。すなわち患者に本発明品約20mlを与え、家庭
においても朝夕二回約30分間ずつ塗布又は貼布さ
せた。48時間後に掻痒は消失し、96時間後に発赤
はほとんど消失し、1週間後に発赤は全く認めら
れなかつた。
熱傷の治療試験
(A) 左前腕外側部に手掌大の発赤腫張と一部小水
疱形成を見た熱湯による熱傷度の47才の婦人
が熱湯による受傷の約1時間後に皮膚科専門医
を訪れた。これに対し直ちに水道水(流水)で
患部を冷却した後、本発明品(2倍濃縮物)を
ガーゼに含ませたものを患部に載せ、その上を
油紙で覆い包帯を施した。24時間後に患部に発
赤腫張の残存を認めたが小水疱は消え、疼痛が
なくなつた。
(B) 熱湯により右足背部に鶏卵大の発赤腫張を起
した熱傷度の30才の男子に対し、同様の処置
を施した。その結果、24時間後に一部に発赤の
残存はあつたが腫張は無くなり、疼痛も無くな
つた。
実施例 2
クリーム状化粧料の調製
ステアリン酸1g、ミツロウ7g、自己乳化型
モノステアリン酸−グリセリン4g、流動パラフ
イン30g、ラノリン0.1g、精製水40gの基材に
対し、4倍濃縮液1gの割合になるように添加
し、常法により混練し、クリーム状化粧料を得
た。これを通常の小型瓶に分注、充填し、販売用
とした。
実施例 3
皮膚用医療剤の調製
ステアリン酸1g、ミツロウ7g、自己乳化型
モノステアリン酸−グリセリン4g、流動パラフ
イン30g、ラノリン0.1g、精製水40gの基材に
対し、4倍濃縮液1gの割合になるように添加
し、更に塩酸ピリドキシン、ガンマーオリザノー
ル、アラントイン、DL−アルフアトコフエロー
ル(ビタミンE)、ミンクオイルの適量を添加し、
皮膚用医療剤を得た。[Table] The resulting sterile supernatant can be used as a dermatological medical agent without being concentrated. However, concentrating as described above has storage and other advantages. Concentrated products with a concentration of 25 times or more or dried products can also be used. Furthermore, it can also be used in combination with creams, ointment bases and other carriers. An example of the results of an analysis of the above-mentioned sterile 4-fold concentrate revealed that it contained various amino acids and vitamins. However, since these analyzes only target general items, it is not possible to produce the medical agent for skin of the present invention even if various components are mixed according to the analytical values. That is, it is presumed that the effective substance of the medical drug for skin is due to unknown components outside the analysis items. The above-mentioned sterile concentrate (4 times concentrated) was proven to be harmless as a result of toxicity tests using chicken embryo tests, and was found to be harmless to the skin in human patch tests and human continuous skin irritation tests using 2 times concentrates. It was proven to be harmless and non-irritating in rabbit eye irritation tests. Furthermore, an antibacterial test revealed that it did not contain any antibiotics. Furthermore, it has been found to have therapeutic effects on age spots, rough skin, fine wrinkles, contact dermatitis, and burns. The dermatological medical agents and cosmetics of the present invention will be explained in more detail below with reference to Examples. Reference Example 1 A culture medium (PH5.0) containing 2.4Kg of glucose, 4.0Kg of skim milk, and 0.4Kg of yeast extract in 800% pure water was sterilized by a conventional method in a 1Kl aerated fermentation tank, and then mixed with the same composition. Culture medium
The seed culture solution was pre-cultured at 28°C for about 30 hours at 10°C in a small aerated stirring fermentation tank and inoculated as a seed culture, and the culture was carried out at 28°C for about 70 hours with aeration and stirring. After fermentation, the culture solution was transferred to MP293 manufactured by Naigai Shokuhin Koki Co., Ltd.
−16 type filter (Filter: Toyo Roshi GL-90,
0.5μ) and the company's MP293-4 type filter (membrane filter: Toyo Roshi TM-2, 0.45μ)
The solid particles and further the bacterial cells were removed. The obtained filtrate was subjected to a reverse osmosis membrane method (RO-T10 type reverse osmosis membrane device manufactured by Bio Engineering Co., Ltd.) to
The mixture was concentrated to obtain a 2-fold concentrate. Repeat the above method until concentrated to 200 and 4
A double concentrate was obtained. These obtained concentrated liquids were sterilized using a plate heat exchanger (manufactured by Iwai Kikai Kogyo Co., Ltd.), filled aseptically into a glass container, and stored under refrigeration (5°C). A powder product obtained by freeze-drying from the sterilized product was mixed with a sterile ointment base material to produce a medical material for the skin. A cream-like cosmetic was also produced from the concentrate. As medical agents and cosmetics,
Each showed excellent effects. This point will be explained in more detail below with reference to Examples. Example 1 Human body patch test Approximately 0.2 g of the 2x concentrate was applied to a 4 cm square patch, and this was applied to 50 women aged 23 to 44 (who had some skin symptoms and went to a dermatology hospital). It was pasted on the inside of the left upper arm and the dorsal paravertebral region of a patient visiting the hospital. The adhesive bond was removed after 48 hours. As a result of the evaluation performed 30 minutes after removal, there were no positive results in the left upper arm medial region or the dorsal paravertebral region. Continuous Human Skin Irritation Test Approximately 5 ml of the 2x concentrate was placed in 10 cm 2 of sterile gauze and tested on 45 women aged 23 to 45 (35 of whom were outpatients at a dermatology hospital with some kind of skin condition). , 10 female employees of the hospital) on the right facial cheek area.
Applied for 15 minutes. This coating treatment was continued for 40 days. As a result, all the subjects showed no reaction, and none of them exhibited abnormal symptoms such as erythema. Rabbit eye irritation test Inject 0.1 ml each of the 2x concentrated solution into the right eye and the blank test solution into the left eye of three white domestic rabbits that were previously confirmed to have no eye abnormalities.
Immediately after instillation, 3, 6, 24, 48, and 72 hours later, both eyes were examined using a slit lamp. As a result, no hyperemia or other abnormalities were observed in the cornea, erythema, or conjunctiva of both eyes during any observation. Treatment trial for age spots Excluding liver disease patients, gynecological patients, and pregnant women, 621 women with facial skin spots attending a dermatology hospital were treated with ozone and steam after washing their faces. After opening the pores, the product of the present invention (a 2-fold concentrate of the sterile supernatant liquid) was made into gauze.
I applied it closely to the area where the stain was generated and covered it with Saran Wrap. Then, infrared irradiation was performed for 15 to 20 minutes to allow the product to penetrate into the skin. This treatment was continued once a week for 3 months. As a result, 363 people (58.4%) found that their symptoms had improved significantly, and 122 people (19.8%) had slightly improved symptoms.
%), 133 people (21.4%) with no improvement recognized,
1 person (0.01%) had worsening, and 2 others (contact dermatitis due to another cause) (0.03%)
%). In this way, the total of those who were greatly improved and those who were slightly improved reached approximately 80%, and of the 363 patients who were greatly improved, approximately 60% had no dark spots at all. Treatment test for rough skin and fine wrinkles The product of the present invention (double concentrate) was used on a trial basis for the treatment of rough skin and fine wrinkles in female patients over 25 years of age attending a dermatology hospital. Usually, women over the age of 30 are concerned about rough skin and fine lines. The skin is most rough, especially at the age of 35 to 40.
Those aged 30 to 35 are the most concerned about fine lines, followed by those aged 40 and over, who tend not to worry about them as there is no significant difference. There, 150 women were examined between the ages of 25 and 30, and 218 women were between the ages of 30 and 35.
248 people aged 35-40, 172 aged 40-45, aged 45 and over
After washing the facial skin of 174 people, a total of 962 people,
The pores are opened using ozone and steam, and then the product of the present invention (double concentration of sterile supernatant liquid) is soaked in gauze and placed over the face, covered with Saran Wrap, and infrared rays are emitted. We tried a method of irradiating the product for 15 to 20 minutes to allow the product to penetrate into the skin. 698 people (73%) reported that their rough skin improved significantly after one treatment, 156 (16%) reported a slight improvement after just one treatment, and 72 (7%) experienced no change. ), no symptoms worsened, and 36 other patients (4%). As skin roughness progresses, fine wrinkles are likely to develop, so it has been found that the product of the present invention, which is effective in treating rough skin, is useful as a cosmetic product for preventing fine wrinkles. Treatment test for contact dermatitis The day after changing from Company A's Eyeshado to Company B's Eyeshado, a patient developed redness and itching on the eyelids on both sides of his face and was diagnosed with contact dermatitis.21
A dermatologist applied gauze containing the product of the present invention (double concentrate) to the affected area of a female aged 30 years old. At that time, only the product of the present invention was used without using steroid preparations, anti-inflammatory agents, or antihistamines. That is, approximately 20 ml of the present invention product was given to the patient, and the patient was allowed to apply or patch the product at home for approximately 30 minutes twice in the morning and evening. The itching disappeared after 48 hours, the redness almost disappeared after 96 hours, and no redness was observed after one week. Burn treatment trial (A) A 47-year-old woman with severe burns caused by boiling water, who experienced palm-sized redness and swelling and some vesicle formation on the outside of her left forearm, visited a dermatologist about 1 hour after the injury caused by boiling water. Ta. Immediately after cooling the affected area with tap water (running water), gauze containing the product of the present invention (double concentrate) was placed on the affected area, and the area was covered with oiled paper and a bandage was applied. After 24 hours, residual redness and swelling were observed in the affected area, but the vesicles disappeared and the pain disappeared. (B) The same treatment was applied to a 30-year-old male with severe burns who had developed redness and swelling on the dorsum of his right leg the size of a hen's egg due to boiling water. As a result, 24 hours later, although some redness remained, the swelling was gone and the pain was gone. Example 2 Preparation of creamy cosmetics Ratio of 1 g of 4x concentrate to base materials of 1 g of stearic acid, 7 g of beeswax, 4 g of self-emulsifying monostearic acid-glycerin, 30 g of liquid paraffin, 0.1 g of lanolin, and 40 g of purified water. A cream cosmetic was obtained by kneading in a conventional manner. This was dispensed and filled into regular small bottles for sale. Example 3 Preparation of medical agent for skin The ratio of 1 g of 4-fold concentrate to the base materials of 1 g of stearic acid, 7 g of beeswax, 4 g of self-emulsifying monostearic acid-glycerin, 30 g of liquid paraffin, 0.1 g of lanolin, and 40 g of purified water. Add appropriate amounts of pyridoxine hydrochloride, gamma oryzanol, allantoin, DL-alphatocopherol (vitamin E), and mink oil,
A medical agent for skin was obtained.
添付の写真図は、本発明のトリコスポロン カ
シワヤマ株の、バレイシヨ抽出液寒天培地におけ
るスライド培養(25℃、3日後)時の形体を示す
ものでしる。第1図は好気的条件下での分節胞子
の、菌糸細胞からの着生状態を示す顕微鏡写真で
ある(×75)。該分節胞子は、分生子柄上に着生
せず、菌糸細胞の隔壁部位から、側状(lateral)
に派生し連鎖している。第2図は、分節胞子の拡
大顕微鏡写真図である(×300)。第3図は、嫌気
的条件下での細胞とその出芽形態を示す顕微鏡写
真図である(×300)。
The attached photograph shows the morphology of the Trichosporon kashiwayama strain of the present invention when cultured on a slide culture (25°C, 3 days later) on a potato extract agar medium. Figure 1 is a micrograph (x75) showing the state of adhesion of segmented spores from hyphal cells under aerobic conditions. The segmental spores do not settle on the conidiophores, but are lateral from the septum of the hyphal cells.
It is derived from and linked to. Figure 2 is an enlarged micrograph of segmented spores (x300). FIG. 3 is a micrograph (×300) showing cells and their budding morphology under anaerobic conditions.
Claims (1)
第4821号)を、PH4.0〜6.0、温度20〜30℃におい
て培地上または培地中で培養し、得られた培養液
から皮膚に対し医療効果を有する物質をうること
を特徴とする皮膚用医療剤の製造法。 2 培地がグルコース、スキムミルク、イースト
エキスからなることを特徴とする特許請求の範囲
1記載の皮膚用医療剤の製造法。 3 培養を好気的条件下で行なうことを特徴とす
る特許請求の範囲2記載の皮膚用医療剤の製造
法。 4 皮膚に対し医療効果を有する物質をうる手段
が、培養液を濾過除菌し、得られた無菌上澄液を
採取することからなる特許請求の範囲1記載の皮
膚用医療剤の製造法。 5 無菌上澄液より水分を蒸散し、濃縮液もしく
はその乾燥物をうることからなる特許請求の範囲
4記載の皮膚用医療剤の製造法。[Scope of Claims] 1. Trichosporon Kashiwayama strain (Feikoken Bibori No. 4821) is cultured on or in a medium at a pH of 4.0 to 6.0 and a temperature of 20 to 30°C. A method for producing a medical agent for skin, characterized by containing a substance having a medical effect on skin. 2. The method for producing a medical agent for skin according to claim 1, wherein the medium comprises glucose, skim milk, and yeast extract. 3. The method for producing a medical agent for skin according to claim 2, wherein the culturing is carried out under aerobic conditions. 4. The method for producing a medical agent for skin according to claim 1, wherein the means for obtaining a substance having a medical effect on the skin comprises filtering and sterilizing the culture solution and collecting the obtained sterile supernatant. 5. The method for producing a medical agent for skin according to claim 4, which comprises evaporating water from the sterile supernatant to obtain a concentrated liquid or a dried product thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61025268A JPS6289623A (en) | 1986-02-07 | 1986-02-07 | Dermal medical agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61025268A JPS6289623A (en) | 1986-02-07 | 1986-02-07 | Dermal medical agent |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP11229479A Division JPS5636419A (en) | 1979-09-01 | 1979-09-01 | Medical treating agent for skin |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6289623A JPS6289623A (en) | 1987-04-24 |
JPH0348166B2 true JPH0348166B2 (en) | 1991-07-23 |
Family
ID=12161280
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP61025268A Granted JPS6289623A (en) | 1986-02-07 | 1986-02-07 | Dermal medical agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6289623A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3704342B2 (en) * | 2003-06-17 | 2005-10-12 | 株式会社オードビー・ジャポン | Moisturizer and skin cosmetics and beauty foods and drinks containing the moisturizer |
-
1986
- 1986-02-07 JP JP61025268A patent/JPS6289623A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS6289623A (en) | 1987-04-24 |
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